Prostate cancer is the most commonly diagnosed nondermatologic cancer in the United States among men. It has been estimated that over 325,000 new cases of prostate cancer are diagnosed in the United States each year, with over 40,000 fatalities annually.
The etiology of prostate cancer involves the effects of androgens as well as inherited genotypes that regulate androgen metabolism. Candidate prostate cancer genes include those involved in androgen metabolism, such as the androgen receptor (Giovannucci et al. Proc. Natl Acad. Sci. USA 1997 94(7):3320-3; Ingles et al. J. Nat. Cancer Inst. 1997 89(2):166-170) or 5-.alpha.-reductase type II (Reichardt et al. Cancer Res. 1995 55(18):3973-5) genes. Additional candidates include members of the cytochrome P450 supergene family involved in androgen metabolism.
One member of this multigene family is CYP3A4, a gene involved in the oxidation of testosterone to 2.beta.-, 6.beta.-, or 15.beta.-hydroxytestosterone (Waxman et al. Arch. Biochemical Pharmacology 1988 263:242-436). Substantial interindividual variability in metabolism of specific compounds by CYP3A4 has been reported (Kleinbloesem et al. Biochemical Pharmacology 1984 33:3721-3724), yet no genetic basis for this variability has been found. CYP3A4 protein has been reported to be expressed in only 61% of prostate tumors (Murray et al. J. Pathology 1995 177:147-152).
Second cancers are uncommon events occurring at a frequency of about 7% in survivors of primary malignant neoplasms. Leukemias are the major type of second cancers resulting from chemotherapy. There are two main forms of treatment-related leukemia, those with chromosome 5 and 7 monosomies induced by alkylating agents, and those with MLL gene translocations and other translocations related to DNA topoisomerase II inhibitors. Since only a minority of patients develop leukemia following chemotherapy, it has been suggested that differences in drug interactions with the host may be the predisposing factors (Boice et al. Proc. AACR 1997 38:645).
Genetic polymorphisms can account for large differences in the pharmacokinetics of chemotherapeutic agents, but metabolism of the majority is polygenetically determined and unimodally distributed. There is a 5- to 20-fold interindividual variability in drug clearance, which is a consequence of genetic and non-genetic factors. CYP3A-mediated first pass metabolism occurs after oral drug administration and has been suggested to contribute to the variability. CYP3A activity can also be modulated by inducers such as rifampin and anticonvulsants, inhibitors such as azole antifungal agents and macrolide antibiotics, by liver disease and by aging (Wilkinson, G. R. J. Pharmacokinet. Biopharm. 1996 24:475-490).
Epipodophyllotoxins are associated with leukemias characterized by translocation of the MLL gene at chromosome band 11q23 and other translocations. The epipodophyllotoxins, etoposide and teniposide and cyclophosphamide, ifosphamide, vinblastine and vindesine are substrates for metabolism by CYP3A.
A variant in the 5' promoter region of the CYP3A4 gene has now been identified. This polymorphism comprises an A.fwdarw.G transition in the nifedipine-specific response element (NFSE) of the gene. Detection of this polymorphism is useful as a biomarker in predicting prostate cancer and epipodophyllotoxin-induced leukemogenesis.